1F1W

SRC SH2 THREF1TRP MUTANT COMPLEXED WITH THE PHOSPHOPEPTIDE S(PTR)VNVQN

Summary for 1F1W

• Entry DOI: 10.2210/pdb1f1w/pdb
• Related: 1F2F
• Descriptor: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE SRC, S(PTR)VNVQN PHOSPHOPEPTIDE (3 entities in total)
• Functional Keywords: src, sh2 domain, phosphopeptide, specificity switch, transferase
• Biological source: Gallus gallus (chicken); More
• Cellular location: Cell membrane (By similarity): P00523
• Total number of polymer chains: 2
• Total formula weight: 12961.50

Authors

Kimber, M.S.,Nachman, J.,Cunningham, A.M.,Gish, G.D.,Pawson, T.,Pai, E.F. (deposition date: 2000-05-20, release date: 2000-07-06, Last modification date: 2024-10-16)

Primary citation

Kimber, M.S.,Nachman, J.,Cunningham, A.M.,Gish, G.D.,Pawson, T.,Pai, E.F.
Structural basis for specificity switching of the Src SH2 domain.
Mol.Cell, 5:1043-1049, 2000

PubMed Abstract: The Src SH2 domain binds pYEEI-containing phosphopeptides in an extended conformation with a hydrophobic pocket, which includes ThrEF1, binding Ile(pY +3). Mutating ThrEF1 to tryptophan switches specificity to an Asn(pY +2) requirement, yielding a biological mimic of the Grb2 SH2 domain. Here we show that the Src ThrEF1Trp SH2 domain mutant binds pYVNV phosphopeptides in a beta turn conformation, which, despite differing conformations of the interacting tryptophan, closely resembles the native Grb2/pYVNV cognate peptide binding mode. The ThrEF1Trp substitution therefore switches specificity by physically occluding the pTyr +3 binding pocket and by providing additional interaction surface area for Asn(pY +2). This demonstrates structurally how novel SH2 domain specificities may rapidly evolve through single amino acid substitutions and suggests how new signaling pathways may develop.

PubMed: 10911998
DOI: 10.1016/S1097-2765(00)80269-5

Experimental method

X-RAY DIFFRACTION (2.1 Å)